Method of converting barbituric acids into stable aqueous solutions



Patented Jan. 12, 1937 UNITED STATES METHOD OF CONVERTING BARBIT'UBIG ACIDS INTO STABLE AQUEOUS SOLU- TIONS Heinrich Gruber, Schonebcrg, a... Berlin,

Germany No Drawing.

Application June '1, 1932, Serial No. 615,951. In Germany June 18, 1931 20 Claims.

This invention relates to improvements in stabilizing aqueous solutions of alkali metal salts of barbituric acids and it comprises methods of stabilizing such aqueous solution by dissolving in 5 the aqueous solvent thereof, n agent capable of stabilizing the alkali metal sa t against hydrolysis by the aqueous solvent, such agent being sometimes incorporated in the aqueous solvent prior to dissolving the alkali metal salt herein and sometimes introduced into an aqueous solution of an alkali metal salt having the said acid and alkali combined in substantially equi-molecular proportions, and it also comprises the preparations so obtained, said preparations being stable aqueous solutions of alkali metal salts of barbituric acids having the said acid and alkali combined in substantially equi-molecular proportions and containing suflicient stabilizing agent, advantageously a pyrazolone compound or like non-' 2o albuminous organic nitrogen compounds, to prevent development of free acid and alkali'and to render the solution stable in storage, said solution being suitable for injection; all as more fully hereinafter set forth and as claimed.

It is well known that substituted barbituric acids are generally diflicultly soluble in water, some being more insoluble than others. Special methods are necessary to prepare aqueous solutions from such acids. Generally the practice is to convert the acid into a derivative which is soluble in or miscible with water, such as the metal salts or organic derivatives thereof. However,

the aqueous solutions of such water-soluble demore or less hydrolyzed, the extentvof hydrolysis.

depending upon the particular barbituric acid combined withthe alkali metal. when hydrolysis occurs free acid is formed, which being in-' soluble, usually appears as a precipitate or deposite; a corresponding amount of free alkali being liberatedin thesolution. I The alkali metal salts of certain barbituric acids, such as the oc substituted acids, readily dissolve in water. But the aqueous solutions'ob- 'tained are unstable and sooner or later become turbid and deposit insoluble matter. This is particularly so with those compounds wherein the hydrocarbon substituent is a non-cyclic (open chain) group containing at least five carbo atoms. Frequently this decomposition is-so spontaneous that it occurs during or shortly after the dissolving of the alkali metal salts of such acids in the water. 5

To prepare stable solutions of barbituric compounds for medicinal use, various methods and compositions have been proposed to obviate the diificulties mentioned ante. In most of them, organic solvents or other barbituric compounds or both are employed in lieu of an aqueous solution and an alkali metal salt, to avoid the dimculties inherent in the combinations of the latter materials; the advantages of aqueous solutions of alkali metal salts being forfeited to avoid unwanted results. On the other hand, to obtain clear solutions of barbituric acid in dilute aqueous alkali lye, heretofore the practice has been to employ an excess of alkali lye to take all the acid into solution. Such aqueous solutions, while satisfactory for some purposes, are not fully desirable for injection purposes. When freshly prepared, although all the barbituric acid may be dissolved, they naturally contain free alkali, that is, an excess of alkali over the-molar amount equivalent to the acid. In this respect, they are less desirable than freshly prepared aqueous solutions of alkali metal salts of barbituric acid, obtained by adding the alkali metal salt to water, although the later solutions deposit insoluble acid on stand-' ing. 1

I have now found that in preparing suitable solutions of barbituric acid compositions, it is not necessary to resort to special organic solvents or special organic derivatives of those acids. That I have discovered simple and advantageous means by which the disadvantages 01'. aqueous solutions of alkali metal salts of such acids can be obviated and by which full advantage can be taken of the excellent water solubility and other desirable properties of such alkali metal salts.

I have found that by incorporating certain hydrotropic substances with the aqueous solvent, it is possible to obtain' aqueous solutions of said alkali salts which are'capable of being diluted with waterand which are stable in storage. For this purpose I employ organic nitrogen-containing hydrotropic substances of non-albuminous nature, soluble in water and capable of stabilizing thealkali metal salt against hydrolysis by the aqueous solvent. By employing suitable amounts of these stabilizing; agents, such as pyrazolones and like non-albuminous organic nitrogen-com, taining compounds, any substantialdevelopment of the barbituric acid or to dilute aqueous solutionsof such alkali metal salts containing the said acid and alkali combined in substantial equi'- molecular proportions, such as a freshly prepared solution in water of the alkali metal salt. The illustrative examples given post set forth typical embodiments of such procedures. Likewise solutions of mixtures of such hydrotropic substances may sometimes be employed. To render the aqueous solutions of said alkali metal salts stable in storage, suificient of the stabilizing agent is added to prevent hydrolysis of the alkali metal salt; the amount in a given instance depending upon the particular hydrotropic substance used. Usually only a small amount of these hydrotropic substances is needed. For instance, when pyrazolones are used relatively small quantities are sufficient to obtain the desired effect. Dimethyl phenyl pyrazolone is typical of the water soluble pyrazolone compound and is quite effective for the present purposes. However, other non-albuminous organic nitrogen-containing compounds such as ureas, amlds of lower fatty acids, etc., may be employed. The urea. and acetamid employed in the illustrative examples given post are typical of such stabilizing agents,

Thus by the present invention, stable aqueous.

solutions of the alkali metal salts of barbituric acid are readily obtained. It is even now possible to produce such stable solutions from those alkali metal salts ofbarbituric acid which have heretofore spontaneously decomposed by hydrolysis when contacted with water. The aqueous solutions of the alkali metal salts of barbituric acids produced by the present invention being stable in' storage and stabilized against hydrolysis of the alkali metal salt, are advantageous for producing solutions for injecting purposes.

Example 1 v10 g. of the sodium salt of the methylpropylcarbin-ethyl-barbituric acid of the formula OHQ'CHLCHi be diluted with water without any deposit being formed.

. Example 2 10.2 g. of isoamyl-ethylbarbituric acid are, dissolved in 22.1 cm. of 2/n soda lye and the small residue of undissolved particles is filtered o'fi. To the resulting fluid 83 g. of a 70 percent acetam-idosolution are added. The end product is a clear, stable solution.

Example 3 20 g. of methylpropyl-carbin-ethyl-barbituric sodium are dissolved in 193 g. of a 20 percent solution of dimethylphenylpyrazolone in water. The product is a stable clear solution.

I claim:

1. As an improved method of preparing stable aqueous solutions of alkali metal salts of substituted barbituric acids, suitable for injection purposes, the process which comprises preparingan aqueous solution of said alkali metal salt having the said acid and alkali combined in substantially equi-molecular proportions and incorporating a non-albuminous, organic nitrogen-containing, hydrotropic substance with the aqueous solvent, said substance being water-soluble and capable of stabilizing the said alkali metal salt against hydrolysis by the aqueous solvent, sufiicient stabilizing agent being incorporated to prevent any substantial development of free acid and alkali and to render theaqueous solution of said alkali metal salt stable in storage.

2. The process of claim I wherein said stable solution is obtained bydissolving the said alkali metal salt in an aqueous solution of the said stabilizing agent, sufiicient stabilizing agent being present to prevent hydrolysis of the salt during the dissolving thereof.

3. The process of claim 1 wherein a sodium salt of an amyl-ethyl barbiturlc acid is dissolved in an aqueous solution containing aminor amount of a pyrazolone dissolved therein.

4. The process of claim 1 wherein the sodium salt of methyl-propyl-carbin-ethyl barbituric acid is dissolved in a 20 per cent aqueous solution of dimethyl-phenyl-pyrazolone.

5 The process of claim 1 wherein the said aqueous solution of the said alkali metal salt is prepared byadding an excess of the said barbituric acid to an aqueous solution of alkali lye containing insufiicient alkali lye to dissolve all the acid and filtering off the undissolved, uncombined acid, to combine substantially all of the alkali with acid and wherein the said aqueous'solution of alkali metal salt having the said acid and alkali combined in substantially equi-molecular proportions so obtained is then diluted with an aqueous solution of said hydrotropic substance to so introduce the stabilizing agent and stabilize the said alkali metal salt so formed.

6. In the preparation of aqueous solutions of al- I kali metal salts of substituted barbituric acids having the said acid and alkali combined in substantially equi-molecularproportions and suitable for injection, the improvement which c'omprises arresting the normal development of free acid and alkali by dissolving in the aqueous solvent a non-albuminous, organic nitrogen-containing hydrotropic agent capable of stabilizing the said alkali metal salt against hydrolysis by the aqueous solvent, suiiicient stabilizing agent being so introduced to render the aqueous preparation stable in storage.

7. The improvement of claim 6 wherein said stabilizing agent is a water solublepyrazolone compound- 8. The improvement of claim 6 wherein said stabilizing agent is dimethyl-phenyl-pyrazolone.

9. The improvement of claim 6 wherein the alkali metal salt so stabilized in aqueous solution is the sodium salt of methyl-propyl-carbinethyl barbituric acid.

10. The improvement of claim wherein the alkali metal salt so stabilized in aqueous solution is a salt of an alkyl substituted barbituric acid having an alkyl group which contains at least 5 carbonatoms.

11. The improyement of claim 6 wherein the,

alkali metal salt so stabilized in aqueous solution is the sodium salt of isoamyl-ethyl barbituric acid.

12. As an improved medicinal preparation suitable for injection and stable in storage, a stable aqueous solution of an alkali metal salt of substituted barbiturie acids having the said acid and 7 present to prevent any substantial development 14. The -'improved preparation of claim 12 wherein said stabilizing agent is a water-soluble pyrazolone compound.

15. The improved preparation of claim 12 wherein said stabilizing agent is dimethyl-phenyl pyrazolone. v

16. The improved preparation ofclaim 12 which comprises the sodium salt of methylpropyl- 'carbin-ethyl-barbituric acid dissolved in an aqueous solution of dimethyl-phenyl pyrazolone.

17. The improved preparation of claim 12 wherein said stabilizing agent is acetamide.

18. The improved preparation of claim 12 which comprises the sodium salt of isoamylethyl-barbituric acid dissolved in an aqueous solution of acetamide.

19. The improved preparation of claim 12 v wherein said stabilizing agent is urea. 

